What is the role of soluble fms-like tyrosine kinase-1 (sFlt-1) in preeclampsia?

What is sFlt-1 in Preeclampsia

sFlt-1 (soluble fms-like tyrosine kinase-1) is an anti-angiogenic protein that serves as the central mediator of preeclampsia's pathophysiology by antagonizing vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), thereby causing the widespread endothelial dysfunction responsible for the disease's clinical manifestations. 1, 2

Mechanism of Action

sFlt-1 functions as a decoy receptor that binds and neutralizes circulating VEGF and PlGF, creating a deficiency of these pro-angiogenic factors in maternal circulation. 1, 2 This angiogenic imbalance triggers systemic endothelial dysfunction affecting multiple organ systems including kidneys, liver, brain, and cardiovascular system. 3

• The stressed, hypoxic placenta releases excessive sFlt-1 into maternal circulation as a pathogenic response to placental ischemia resulting from failed spiral artery remodeling. 1, 2
• VEGF normally promotes vasodilation by increasing nitric oxide and prostacyclin production; sFlt-1 antagonism reduces these vasodilators, leading to vasoconstriction and hypertension. 3
• Administration of sFlt-1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis—the pathognomonic renal lesion of preeclampsia—demonstrating its causal role. 4

Clinical Manifestations Mediated by sFlt-1

The endothelial dysfunction caused by excess sFlt-1 produces the characteristic multi-organ features of preeclampsia:

• Renal involvement: Glomerular endotheliosis develops, causing proteinuria and decreased glomerular filtration rate. 3
• Hepatic involvement: Reduced perfusion causes necrosis and hemorrhage, manifesting as elevated liver enzymes and epigastric pain. 3
• Cerebral involvement: Cerebral edema leads to headache, visual disturbances, and seizures. 3
• Cardiovascular effects: Increased vascular resistance and hypertension result from widespread vasoconstriction. 2

Placental-Specific Variant

A specific splice variant, sFlt-1 e15a, is the main form secreted from the placenta and is significantly elevated in preeclampsia. 5 This variant is unique to humans and higher-order primates, which may explain why preeclampsia is a uniquely human disease. 5 Overexpression of sFlt-1 e15a in mice recapitulates the complete preeclamptic phenotype during pregnancy. 5

Clinical Utility as a Biomarker

The sFlt-1/PlGF ratio reflects underlying pathophysiology and serves as a validated biomarker for preeclampsia diagnosis and risk stratification. 1

• The ratio can help rule out preeclampsia requiring delivery within 7-14 days in suspected cases between 20-34+6 weeks gestation. 1
• In early-onset preeclampsia (≤35 weeks), an sFlt-1/PlGF ratio ≥85 demonstrates 74% sensitivity and 97% specificity for predicting adverse outcomes, with a positive predictive value of 96%. 6
• Women with any adverse outcome have a median ratio of 227.6 versus 14.4 in those without adverse outcomes. 6
• Patients delivering within 7 days have a median ratio of 260.0 compared to 14.4 for those delivering after two weeks or more. 6

Therapeutic Implications

The central role of sFlt-1 makes it a potential therapeutic target, though interventions remain experimental:

• Dextran sulfate apheresis can reduce circulating sFlt-1 levels in early preterm preeclampsia, with pilot studies showing reduced proteinuria and stabilized blood pressure without major adverse consequences. 7, 8
• A single apheresis treatment reduces sFlt-1 in a dose-dependent fashion, and multiple treatments have prolonged pregnancy by 15-23 days in case series. 8
• These results require cautious interpretation as this strategy has not been evaluated through larger randomized controlled trials. 7

Distinguishing Preeclampsia from Other Placental Disorders

sFlt-1 elevation is specific to preeclampsia with maternal syndrome, not merely placental insufficiency:

• sFlt-1 levels are increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates, despite both conditions sharing placental hypoxia. 9
• This distinction demonstrates that sFlt-1 contributes specifically to the maternal vascular manifestations of preeclampsia rather than fetal growth restriction alone. 9
• PlGF is decreased in both conditions, but only preeclampsia shows the characteristic sFlt-1 elevation. 9

Pathophysiological Context

sFlt-1 represents the molecular link between Stage 1 (abnormal placentation) and Stage 2 (maternal syndrome) of preeclampsia's two-stage disease process. 1, 2 The Society for Maternal-Fetal Medicine and Preeclampsia Foundation recognize that biomarkers including sFlt-1 have been investigated for their ability to predict both early- and late-onset preeclampsia. 7